New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Atherosclerosis in young Brazilians suffering violent deaths: a pathological study

<p>Abstract</p> <p>Background</p> <p>Atherosclerosis is the leading cause of coronary heart disease and ischemic stroke, which can cause sudden death in adulthood. In general, the clinical manifestations of cardiovascular diseases are caused by atherosclerosis, which is a process that starts during middle age. More recent studies indicate that the atherosclerotic process begins during childhood.</p> <p>Methods</p> <p>To evaluate the extent of atherosclerotic disease in young Brazilians, we conducted a study of the pathological alterations in the major arteries of victims of violent death. Samples of the right carotid artery, left coronary artery, and thoracic aorta of young victims of violent death were analyzed and graded in accordance with the histological atherosclerotic lesion types proposed by the American Heart Association. Samples were collected from 100 individuals who had died from external causes, aged from 12 to 33 years.</p> <p>Results</p> <p>The majority of cases (83%) were male, and 66% of deaths were homicides caused by firearms. The median age was 20.0 years and mean body mass index was 20.9 kg/m². Of the right carotid artery specimens, 3% were normal, 55% had type I, 40% had type II, 1% had type III, and 1% had type IV atherosclerotic lesions. Of the left coronary artery specimens, 5% were normal, 48% had type I, 41% had type II, 3% had type III, and 3% had type IV lesions. Of the thoracic aorta specimens, none were normal, 13% had type I, 64% had type II, 22% had type III, and 1% had type IV lesions. Overall, 97.34% of arteries examined had some degree of atherosclerosis. The most common histological type was type II (foam cells). No thoracic aorta specimens were normal, and the coronary artery specimens had the most atherosclerosis.</p> <p>Conclusions</p> <p>Our results show a high prevalence of atherosclerotic lesions among young people in Brazil. Intervention should be undertaken to decrease the rate of sudden cardiac death in the adult population.</p

Outbreak of COVID-19 and SARS in mainland China: a comparative study based on national surveillance data

Objective To compare the epidemiological characteristics and transmission dynamics in relation to interventions against the COVID-19 and severe acute respiratory syndrome (SARS) outbreak in mainland China. Design Comparative study based on a unique data set of COVID-19 and SARS. Setting Outbreak in mainland China. Participants The final database included 82 858 confirmed cases of COVID-19 and 5327 cases of SARS. Methods We brought together all existing data sources and integrated them into a comprehensive data set. Individual information on age, sex, occupation, residence location, date of illness onset, date of diagnosis and clinical outcome was extracted. Control measures deployed in mainland China were collected. We compared the epidemiological and spatial characteristics of COVID-19 and SARS. We estimated the effective reproduction number to explore differences in transmission dynamics and intervention effects. Results Compared with SARS, COVID-19 affected more extensive areas (1668 vs 230 counties) within a shorter time (101 vs 193 days) and had higher attack rate (61.8 vs 4.0 per million persons). The COVID-19 outbreak had only one epidemic peak and one epicentre (Hubei Province), while the SARS outbreak resulted in two peaks and two epicentres (Guangdong Province and Beijing). SARSCoV-2 was more likely to infect older people (median age of 52 years), while SARS-CoV tended to infect young adults (median age of 34 years). The case fatality rate (CFR) of either disease increased with age, but the CFR of COVID-19 was significantly lower than that of SARS (5.6% vs 6.4%). The trajectory of effective reproduction number dynamically changed in relation to interventions, which fell below 1 within 2 months for COVID-19 and within 5.5 months for SARS. Conclusions China has taken more prompt and effective responses to combat COVID-19 by learning lessons from SARS, providing us with some epidemiological clues to control the ongoing COVID-19 pandemic worldwid

Physical Activity Attenuates the Genetic Predisposition to Obesity in 20,000 Men and Women from EPIC-Norfolk Prospective Population Study

Shengxu Li and colleagues use data from a large prospective observational cohort to examine the extent to which a genetic predisposition toward obesity may be modified by living a physically active lifestyle

A Latent Variable Partial Least Squares Path Modeling Approach to Regional Association and Polygenic Effect with Applications to a Human Obesity Study

Genetic association studies are now routinely used to identify single nucleotide polymorphisms (SNPs) linked with human diseases or traits through single SNP-single trait tests. Here we introduced partial least squares path modeling (PLSPM) for association between single or multiple SNPs and a latent trait that can involve single or multiple correlated measurement(s). Furthermore, the framework naturally provides estimators of polygenic effect by appropriately weighting trait-attributing alleles. We conducted computer simulations to assess the performance via multiple SNPs and human obesity-related traits as measured by body mass index (BMI), waist and hip circumferences. Our results showed that the associate statistics had type I error rates close to nominal level and were powerful for a range of effect and sample sizes. When applied to 12 candidate regions in data (N = 2,417) from the European Prospective Investigation of Cancer (EPIC)-Norfolk study, a region in FTO was found to have stronger association (rs7204609∼rs9939881 at the first intron P = 4.29×10−7) than single SNP analysis (all with P>10−4) and a latent quantitative phenotype was obtained using a subset sample of EPIC-Norfolk (N = 12,559). We believe our method is appropriate for assessment of regional association and polygenic effect on a single or multiple traits

Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.Peer reviewe

Publisher Correction: A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids

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Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels

Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log10Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10-5) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets

Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10−8), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits

Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes

ObjectiveProinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology.Research design and methodsWe have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates.ResultsNine SNPs at eight loci were associated with proinsulin levels (P &lt; 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets.ConclusionsWe have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis